Hepatitis B is one of global diseases. According to the WHO's report, about 30% of the population in the world, i.e., 1.8 billion, are infected by hepatitis B virus, among them about 350 millions are chronically infected. The latter exhibit a continuous viremia, and the virus level is 100-1000 times higher than that of AIDS virus (HIV) or hepatitis C virus (HCV). China is one of the high-risk regions in the world, with carriers of hepatitis B virus being about 10% of the total population, i.e., about 120 millions, and patients of chronic hepatitis being about 30 millions. Most cases of hepatitis B were infected during perinatal period, developed during adolescence, and exacerbated in young adults. Thus, it mainly endangers young adults. Most patients are spontaneously cured after infection, while some patients are not cured, and liver cirrhosis and liver cancer are developed. It is estimated that at least 500 thousands patients of chronic hepatitis die of liver cirrhosis and liver cancer. Hepatitis B virus (HBV) is a human carcinogen only next to tobacco.
At present, the main means for controlling prevalence of hepatitis B is the global immunization program practiced by WHO. However, because of (1) the program employs preventive vaccine, which is ineffective to infected persons; (2) 5-15% uninfected neonates do not respond to said vaccine; and (3) the inoculation rate is low, and according to the statistics in 1999, the inoculation rate of neonates in high-risk regions in the world is only 62%. Thus, during a relatively long period in future, hepatitis B will still be one of the most serious diseases harmful to people's health.
The positive rates of HBV core antigen (HBcAg) in hepatic carcinoma and paraneoplastic tissues are 62.5% and 29.2% respectively. At present, it has been proven that: (1) as a hepatotropic virus, HBV cannot directly cause damage of liver cells, rather, the pathology and clinical results of HBV infection depend on immunologic mechanism; and (2) as an intracellular infection, the chronic persistent infection state is mainly associated with the relatively weakness of the cellular immune response in vivo, wherein HBV-specific cytotoxic T lymphocyte (CTL) response determines the final result of HBV infection. If a patient has a high level of CTL activity after HBV infection, viruses will be eliminated in vivo and the patient will recover; while if a patient has a low or undetectable level of CTL activity after HBV infection, the patient will be in a chronic persistent infection state, and a liver cirrhosis or liver cancer will be further developed. Thus, the chronic HBV persistent infection state could be treated and the relevant secondary liver cirrhosis and liver cancer could be prevented by overcoming the immune tolerance in patients with HBV persistent infection and initiating the HBV specific CTL response in vivo.
F. V. Chisari in Scripps Institute (U.S.) filed four patent applications (U.S. Pat. No. 6,235,288, U.S. Pat. No. 5,932,224, U.S. Pat. No. 5,840,303, and U.S. Pat. No. 5,788,969) based on his own studies. These patent applications all relate to CTL epitopes determined on HBV antigens. These epitopes are separately from core antigens, surface antigens, polymerases, and X antigens. These parts or structures are recognizable by CTL induced by HBV. Jiangxi Nanchang Medical College (China) filed an application, seeking to protect a plasmid DNA vaccine comprising Pre-S2 and HBsAg, which stimulates cellular immunity and humoral immunity and is useful for the prevention and treatment of hepatitis B.
At present, there is no specific therapeutic method for treatment of chronic HBV persistent infection state (including virus carrier, chronic persistent hepatitis, and chronic active hepatitis). Interferons (IFN-α/β, IFN-γ) and tumor necrosis factors (TNF-α) are proven to be able to down regulate the replication and gene expression of HBV in infected cells, and are sensitive to replicating DNA intermediates and transcription template, but they cannot eliminate virus. Lamivudine (3TC) is the first nucleoside medicament in clinical use for inhibiting virus replication, which is able to reduce viremia for up to 2 times log, but can hardly eliminate virus, because the virus titer in E antigen positive carriers is more than 108. In fact, no treated patient has been found to become HBsAg negative. Hence, it is badly in need to develop an effective means for treating chronic HBV persistent infection state.